2-Amino-quinolin-4-one-3-phosphonic acid esters

ABSTRACT

Anti-allergic 2-amino-quinolin-4-one-3-phosphonic acid esters are prepared by reacting an isatoic anhydride with the carbanion resulting from the treatment of an organo-methane phosphate with a proton abstracting agent.

This invention relates to chemical compounds which are2-amino-quinolin-4-one-3-phosphonic acid esters, to their preparationand to their use as pharmacological agents, particularly asanti-allergic agents.

In accordance with one aspect of the invention, the compounds of theformula I: ##STR1## wherein R^(o) is hydrogen, alkyl of 1 to 6 carbonatoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in which thecyloalkyl is of 3 to 6 carbon atoms and the alkyl portion is of 1 or 2carbon atoms, or ##STR2## n is 0 or 1, Y and Y' are independentlyhydrogen, halo of atomic weight of from 18 to 80, i.e., fluoro, chloroor bromo, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms ortrifluoromethyl,

R and R' are independently hydrogen, halo of atomic weight of from 18 to80, i.e., fluoro, chloro or bromo, alkyl of 1 to 4 carbon atoms, alkoxyof 1 to 4 carbon atoms, nitro or trifluoromethyl, with the proviso thatonly one of R and R' can be from the group consisting of nitro andtrifluoromethyl, or R and R' together form 6,7-methylenedioxy, and

R₁ and R₂ are independently alkyl of 1 to 4 carbon atoms,

With the further proviso that the unsaturation in any alkenyl or alkynylis on other than the alpha carbon atom, are prepared by reacting anisatoic anhydride of the formula II: ##STR3## wherein R^(o), R' and Rare as defined, with a compound of the formula III: ##STR4## wherein R₁and R₂ are as defined above and M is a cation derived from a protonabstracting agent, in the presence of an inert organic solvent, andtreating the resulting reaction product with a proton source.

The preparation of Compounds I by reacting a Compound II with a CompoundIII may be carried out at temperatures generally in the range of from20° C. to 200° C. in an inert organic solvent of conventional type,desirably an aprotic solvent, and under essentially anhydrousconditions. Examples of preferred solvents include dimethylacetamide,dimethylformamide and tetrahydrofuran, more preferablydimethylacetamide. Preferred temperatures are generally in the range offrom 50° C. to 150° C. and it is usually preferred to initiate thereaction at a temperature in the range of from about 50° C. to 100° C.and then complete the reaction at a higher temperature above 100° C. upto 150° C. The mol ratio of Compound III to Compound II is not criticaland is suitably in the range of 0.8:1 to 2:1, preferably about 1:1.Reaction times may vary fairly widely and can be typically of the orderof 2 to 30 hours, more usually 5 to 20 hours. The resulting reactionproduct is treated in a conventional manner with a proton source toreadily obtain the Compounds I. A wide variety of proton sources areknown and may be employed, but it is generally preferred to employaqueous mineral acid such as hydrochloric acid. The product of theformula I may be isolated and recovered from the resulting reactionmixture by working up by conventional techniques including, withoutlimitation, crystallization, distillation and column chromatography. Thereaction mixtures tend to be more complex when R^(o) is hydrogen andsuch products of the formula I may be readily recovered by columnchromotography.

The compound of the formula III is prepared in situ by reacting acompound of the formula IIIA: ##STR5## wherein R₁ and R₂ are as abovedefined, with a proton abstracting agent in an organic solvent which isof the type suitable for the reaction of Compounds II and III. Reactiontemperatures may be generally of the order of from minus 100° C. to plus150° C., but are preferably in the range of from 10° C. to 50° C. Theproton abstracting agents are those which will dislodge a hydrogen atomfrom the methylene moiety of Compounds IIIA to result in the ionicproduct III with which the Compound II reacts to yield the desiredCompound I. Such agents are of well known types and are represented bythe stronger bases such as the alkali metal hydrides, the butyl lithiumsand tertiary amines with the alkali metal hydrides being particularlypreferred, e.g., sodium hydride and potassium hydride. In general, M ispreferably an alkali metal, particularly sodium or potassium. The phrase"derived from a proton abstracting agent" as used in connection with thedefinition of M is meant to designate the cation present in the protonabstracting agent and freed as a result of the reaction with thecompound IIIA, e.g., sodium when sodium hydride is used, or the cationformed and resulting from such reaction, e.g., the ammonium ion when atertiary amine is employed, as the case may be. The mol ratio ofabstracting agent to the Compounds III may vary fairly widely but ismost suitably at least about 0.8 to 1 and preferably between 0.9:1 to1.5:1, more preferably 1:1 in the preferred modes of conducting thereaction. The resulting compound of the formula III in the organicsolvent in which it is formed is used in preparing Compounds I by mixingsuch solution with Compound II or a solution of Compound II.

As will be evident, the Compounds I may be prepared in accordance withthe reactions above-described by combining Compounds II, IIIA and aproton abstracting agent in an organic solvent and either: i) regulatingthe temperature to form the Compound III without substantial reactionwith Compound II followed by increasing the temperature to form theCompound I; or ii) establishing a temperature within the range of from20° C. to 150° C., whereby the Compounds I are prepared simultaneouslywith and in the presence of the formation of Compounds III. It is,however, preferred that the Compounds III being prepared prior tosubjecting to conditions whereby such Compounds III react with CompoundsII, and preparation of such Compounds III in the absence of Compounds IIis usually the more preferred manner of preparation.

The compounds of the formula II and IIIA are each either known per se ormay be prepared from known materials by procedures established for theknown compounds.

The compounds of formula I, in accordance with another aspect of thepresent invention, are useful because they possess pharmacologicalactivity in animals. In particular, they possess disodium chromoglycate(DSCG)-like activity, in particular histamine release inhibitingactivity, and are therefore useful in the treatment of allergicconditions, such as allergic asthma, as indicated in the passivecutaneous anaphylaxis test in the rat. Female rats (180-200 g) aresensitized by intramuscular administration of 2 mg of egg albumin (MerckNr. 967) dissolved in 0.1 ml of physiological saline and 0.5 ml ofHaemophiluspertussis vaccine (Schweizerisches Serum and Impfinstitut,Bern; Nr. 115 325; 4 × 10¹⁰ organism/ml) intraperitoneally. Fourteendays later, the animals are exsanguinated, the blood centrifuged, theserum collected and deep frozen. The serum thus obtained (anti-serum) isinjected intradermally (0.1 ml of a 1:2 diluted serum per injectionsite) at four sites on the backs of untreated, female rats. Twenty-fourhours later each rat is administered 3.2 mg/kg i.v. or 32 mg/kg p.o. ofthe test compound, and either immediately or 5 or 30 minutes afterwards,in the case of intravenous administration, or 60 minutes afterwards, inthe case of oral administration, afterwards egg albumin (5 mg/ml i.v.)dissolved in physiological saline containing 0.25% Evans Blue dye (MerckNr. 3169). The egg albumin elicits a cutaneous anaphylactic reaction,the intensity of which is proportional to the extent to which the EvansBlue dye diffuses into the tissue surrounding each of the foursensitisation sites. Thirty minutes after the administration of the eggalbumin, the rats are killed with ether, the underside of the skin ofthe back of each animal is exposed and the diameter of the areas of bluedye surrounding each of the four sensitisation sites are measured. Eachdose of test compound is investigated in between four and six rats andthe mean diameter compared with the mean value obtained in foursolvent-treated control rats. The percentage inhibition is taken as thepercentage of the mean diameter in the test animals relative to the meandiameter in the controls.

The DSCG-like activity, in particular histamine release inhibitingactivity, can be confirmed by inhibition of histamine release in the ratperitoneal mast cell test, basically as described by Kusner et al., J.Pharmacol. Exp. Therap. 184, 41-46 (1973), with the followingmodification: after sedimentation of the mast cells by centrifugation at350 × g and 4° C, the sediments are taken up in 1 ml of Hank's balancedsalt solution (HBSS) (buffered to a pH of 6.9) and pooled. The resultingsuspension is centrifuged, washed again with HBSS and sedimented. Thethus purified mast cells are prepared as 2 ml suspensions in HBSS. Tothese are added either 2 ml of HBSS, to determine the spontaneoushistamine release, or 2 ml of HBSS and 2.24 ug of compound 48/80(N-methylhomoanisylamineformaldehyde condensate; a histamine liberatorfrom Burroughs Wellcome and Co. Inc., Tuckahoe, N.Y. USA), to determinethe 48/80 induced histamine release, or 2 ml of HBSS with 2.24 ug of48/80 and from 18 to 180 ug/ml of the test compound, to determine the48/80 induced histamine release in the presence of the test compound.

The 48/80 induced histamine release minus the spontaneous histaminerelease is taken as 100% histamine release. The 48/80 induced histaminerelease in the presence of the test compound minus the spontaneoushistamine release is then compared with the 100% value to determine thepercentage inhibition by the test compound. [The histamine determinationis effected in conventional manner, for example as described in theabove-mentioned Kusner et al. article, or in Kusner and Herzig, Advancesin Automated Analysis, 492 (1971)].

For the above-mentioned use, the dosage administered will, of course,vary depending on the compound employed, mode of administration andtreatment desired. However, satisfactory results are generally obtainedon administration at a daily dosage of from about 1 to 100 mg/kg ofanimal body weight, conveniently given in divided doses two to fourtimes daily, or in sustained release form. For the larger mammals, thetotal daily dosage is in the range of from about 60 to 1000 mg of thecompound admixed with a solid or liquid pharmaceutical carrier, foradministration orally, and divided dosage forms comprise 15 to 500milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier.

A representative formulation for administration 2 to 4 times a day fortreatment of allergic asthma is a capsule prepared by standardtechniques to contain the following:

    ______________________________________                                        Ingredient            Weight (mg)                                             ______________________________________                                        2-amino-1-methyl-quinolin-4-one-                                                                     80                                                     3-phosphonic acid diethyl ester                                               Kaolin                210                                                     ______________________________________                                    

The following examples are given for purposes of illustration only.

EXAMPLE 1 2-amino-1-methyl-quinolin-4-one-3-phosphonic acid diethylester ##STR6##

To a solution of 8.8 g. of diethyl cyanomethane phosphate in 75 ml. ofanhydrous dimethylacetamide is added portionwise 2.1 g. of pentanewashed 56% sodium hydride whereby hydrogen gas is released. Theresulting solution is stirred at room temperature for 15 minutes. Thereis then added a solution of 8.8 g. of N-methyl isatoic anhydride in 75ml. of dimethylacetamide causing the release of carbon dioxide. Theresulting solution is then heated over a period of 30 minutes to 120° C.and maintained at such temperature for 4 hours. The dimethylacetamide isstripped off in vacuo, water added to the oily residue and the aqueousphase is acidified with 2N. hydrochoroic acid to obtain an oil which isextracted into ethyl acetate, washed with saturated sodium chloridesolution, dried, treated with charcoal, filtered and evaporated to anoil which is treated with ether to obtain crystals which are collectedby filtering, washed with ether and twice crystallized from methylenechloride on exchanging for ether to obtain on drying at 100° C.2-amino-1-methyl-quinolin-4-one-3-phosphonic acid diethyl ester, m.p.191°-193° C.

EXAMPLE 2

Following the procedure of Example 1, the following compounds areprepared:

A. 2-amino-1-propargyl-quinolin-4-one-3-phosphonic acid diethyl ester.

B. 2-amino-1-allyl-quinolin-4-one-3-phosphonic acid diethyl ester.

C. 2-amino-1-methyl-6-chloro-quinolin-4-one-3-phosphonic acid diethylester, m.p. 203°-206° C.

D. 2-amino-1-(p-chlorobenzyl)-quinolin-4-one-3-phosphonic acid diethylester.

E. 2-amino-1-methyl-6,7-dimethoxy-quinolin-4one-3-phosphonic aciddiethyl ester.

F. 2-amino-1-phenyl-quinolin-4-one-3-phosphonic acid diethyl ester.

G. 2-amino-1-cyclopropylmethyl-quinolin-4-one-3-phosphonic acid diethylester.

H. 2-amino-quinolin-4-one-3-phosphonic acid diethyl ester.

I. 2-amino-8-methyl-quinolin-4-one-3-phosphonic acid diethyl ester.

J. 2-amino-1-methyl-6,7-methylenedioxy-quinolin-4-one-3-phosphonic aciddiethyl ester.

K. 2-amino-1-benzyl-quinolin-4-one-3-phosphonic acid diethyl ester, m.p.137°-140° C.

Pharmaceutical compositions provided by the invention and useful fortreating allergic conditions due to histamine release contain a compoundof the formula IP as active ingredient and one or more conventionalpharmaceutically acceptable carriers, and such other conventionaladjuvants as may be desired or necessary. Such compositions may be inconventional orally administerable forms such as tablets, capsules,granules, dispersible powders, elixirs, syrups, suspensions and the likeor in conventional parenterally administerable forms such as aninjectable sterile solution, suspension or the like, e.g., a sterileinjectable aqueous suspension. Such compositions including applicableunit dosage forms thereof may be prepared according to any method knownin the art for the manufacture of pharmaceutical compositions. Ingeneral, the compositions of the invention adapted for either oral orparenteral administration may contain from 1% to 90% by total weight ofactive ingredient in combination with the carrier, more usually 3% to70%. The preferred unit dosage forms are the essentially solid formsadapted for oral administration, e.g., tablets or capsules.

What is claimed is:
 1. A compound of the formula: ##STR7## wherein R^(O)is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbonatoms, alkynyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbonatoms, cycloalkylalkyl in which the cycloalkyl is of 3 to 6 carbon atomsand the alkyl portion is of 1 or 2 carbon atoms, or ##STR8## n is 0 or1, Y and Y' are independently hydrogen, fluoro, chloro, or bromo, alkylof 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms ortrifluoromethyl,R and R' are independently hydrogen, fluoro, chloro,bromo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms,nitro or trifluoromethyl, with the proviso that only one of R and R' canbe from the group consisting of nitro and trifluoromethyl, or R and R'together form 6,7-methylenedioxy, and R₁ and R₂ are independently alkylof 1 to 4 carbon atoms, with the further proviso that the unsaturationin any alkenyl or alkynyl is on other than the alpha carbon atom.
 2. Acompound of claim 1 in which R^(O) is hydrogen.
 3. A compound of claim 1in which R^(O) is alkyl.
 4. A compound of claim 1 in which R^(O) isalkenyl.
 5. A compound of claim 1 in which R^(O) is alkynyl.
 6. Acompound of claim 1 in which R^(O) is cycloalkyl or cycloalkylalkyl. 7.A compound of claim 1 in which R^(O) is ##STR9##
 8. A compound of claim7 in which n is
 1. 9. A compound of claim 1 in which R and R' areindependently hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbonatoms, alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl.
 10. Acompound of claim 1 in which R and R' together form 6,7-methylenedioxy.11. The compound of claim 1 which is2-amino-1-methylquinolin-4-one-3-phosphonic acid diethyl ester.
 12. Thecompound of claim 1 which is 2-amino-1-allylquinolin-4-one-3-phosphonicacid diethyl ester.
 13. The compound of claim 1 which is2-amino-1-methyl-6-chloro-quinolin-4-one-3-phosphonic acid diethylester.
 14. The compound of claim 1 which is2-amino-1-(p-chlorobenzyl)-quinolin-4-one-3-phosphonic acid diethylester.
 15. The compound of claim 1 which is2-amino-1-methyl-6,7-dimethoxy-quinolin-4-one-3-phosphonic acid diethylester.
 16. The compound of claim 1 which is2-aminoquinolin-4-one-3-phosphonic acid diethyl ester.
 17. The method oftreating allergic conditions due to histamine release comprisingadministering to a mammal in need of such treatment an allergy treatingeffective amount of a compound of claim
 1. 18. The method of claim 17 inwhich R^(O) is hydrogen.
 19. The method of claim 17 in which R^(O) isalkyl.
 20. The method of claim 17 in which R^(O) is alkenyl.
 21. Themethod of claim 17 in which R^(O) is alkynyl.
 22. The method of claim 17in which R^(O) is cycloalkyl or cycloalkylalkyl.
 23. The method of claim17 in which R^(O) is ##STR10##
 24. The method of claim 23 in which nis
 1. 25. The method of claim 23 in which n is
 0. 26. The method ofclaim 17 in which the compound is2-amino-1-methyl-quinolin-4-one-3-phosphonic acid diethyl ester.
 27. Themethod of claim 17 in which the compound is2-amino-1-allyl-quinolin-4-one-3-phosphonic acid diethyl ester.
 28. Themethod of claim 17 in which the compound is2-amino-1-methyl-6-chloro-quinolin-4-one-3-phosphonic acid diethylester.
 29. The method of claim 17 in which the compound is2-amino-1-methyl-6,7-dimethoxy-quinolin-4-one-3-phosphonic acid diethylester.
 30. The method of claim 17 in which the compound is2-amino-quinolin-4-one-3-phosphonic acid diethyl ester.
 31. The methodof claim 17 in which the compound is2-amino-1-benzyl-quinolin-4-one-3-phosphonic acid diethyl ester.
 32. Thecompound of claim 1 which is2-amino-1-benzyl-quinolin-4-one-3-phosphonic acid diethyl ester.
 33. Apharmaceutical composition comprising in unit dosage form apharmaceutically acceptable carrier and an amount effective to treatallergic conditions due to histamine release of a compound of claim 1.34. A composition of claim 33 in which R^(O) is hydrogen.
 35. A compoundof claim 33 in which R^(O) is alkyl.
 36. A composition of claim 33 inwhich R^(O) is alkenyl.
 37. A composition of claim 33 in solid unitdosage form containing the compound in an amount of from 15 to 500milligrams.